Kratom-induced acute liver injury: A case study and the importance of herbal supplement regulation.

Alternative medicine supplements have become the second most common cause of drug-induced liver injury (DILI) in the US. Kratom is a herbal supplement that is popular for its psychotropic and opioid-like activity. It has become increasingly available in western countries, which often have no specific regulations on its use. However, reports of adverse events linked to kratom use have been increasing; it has been implicated in acute liver injury (mostly cholestatic), acute liver failure, organ dysfunction, toxicity, coma, seizures, and death. Herein, we aim to increase healthcare provider and public awareness of the risks posed by kratom and ultimately support increased regulation of its use.

U.S. Cooperative Extension's response to substance misuse: A scoping review.

Background: The U.S. has experienced exponential growth in overdose fatalities over the past four decades and more than 22 million people are currently living with a substance use disorder (SUD). While great strides have been made in advancing the science of SUD prevention and treatment, proven programs and interventions are not commonly disseminated at scale in impacted communities. The U.S. Cooperative Extension System (Extension) has been recognized as a valued partner in addressing SUD in communities. Federal funding supporting Extension's response to the opioid epidemic reached $35 million in 2021 primarily through two grant programs: the United States Department of Agriculture's (USDA) Rural Health and Safety Education program; and the Substance Abuse and Mental Health Services Administration (SAMHSA) Rural Opioid Technical Assistance (ROTA) grants. The primary objective of this scoping review was to identify the range of Extension activities aimed at mediating substance misuse. Methods: Authors utilized the PRISMA-SCR model to complete this scoping review. Due to the nature of Extension work and the expectation that few activities would be cited in the peer-reviewed literature, the scoping review included a search of peer-reviewed databases, Extension websites for each state and U.S. territory, and the utilization of a web search engine. Upon initial analysis of records returned, authors noted a discrepancy between results returned and the number of states receiving ROTA grants. Thus, authors supplemented the PRISMA-SCR review protocol with a systematic procedure for investigating ROTA funded activities not readily apparent in the peer-reviewed or grey literature. Results: A total of 87 records met inclusion criteria. Findings included seven peer-reviewed articles and 80 results from the grey literature. An additional 11 ROTA grantees responded to requests for information regarding state level activities. Conclusions: Nationwide, Extension has scaled multiple efforts to address SUD operating through a loose confederation of organizations connected to the land-grant system. Most activities are funded by federal grants and focus on state-sponsored training and resource sharing. The volume of effort is significant, however, implementation at the community-level has been slow. Significant opportunities exist for local adoption of evidence-based practices aimed at mitigating SUD.

Psychological Health and Drugs: Data-Driven Discovery of Causes, Treatments, Effects, and Abuses.

Mental health issues can have significant impacts on individuals and communities and hence on social sustainability. There are several challenges facing mental health treatment; however, more important is to remove the root causes of mental illnesses because doing so can help prevent mental health problems from occurring or recurring. This requires a holistic approach to understanding mental health issues that are missing from the existing research. Mental health should be understood in the context of social and environmental factors. More research and awareness are needed, as well as interventions to address root causes. The effectiveness and risks of medications should also be studied. This paper proposes a big data and machine learning-based approach for the automatic discovery of parameters related to mental health from Twitter data. The parameters are discovered from three different perspectives: Drugs and Treatments, Causes and Effects, and Drug Abuse. We used Twitter to gather 1,048,575 tweets in Arabic about psychological health in Saudi Arabia. We built a big data machine learning software tool for this work. A total of 52 parameters were discovered for all three perspectives. We defined six macro-parameters (Diseases and Disorders, Individual Factors, Social and Economic Factors, Treatment Options, Treatment Limitations, and Drug Abuse) to aggregate related parameters. We provide a comprehensive account of mental health, causes, medicines and treatments, mental health and drug effects, and drug abuse, as seen on Twitter, discussed by the public and health professionals. Moreover, we identify their associations with different drugs. The work will open new directions for a social media-based identification of drug use and abuse for mental health, as well as other micro and macro factors related to mental health. The methodology can be extended to other diseases and provides a potential for discovering evidence for forensics toxicology from social and digital media.

Dantrolene sodium fails to reverse robust brain hyperthermia induced by MDMA and methamphetamine in rats.

RATIONALE: Hyperthermia induced by psychomotor stimulants may cause leakage of the blood-brain barrier, vasogenic edema, and lethality in extreme cases. Current treatments such as whole-body cooling are only symptomatic and a clear need to develop pharmacological interventions exists. Dantrolene sodium, a peripheral muscle relaxant used in the treatment of malignant hyperthermia, has been proposed as potentially effective to treat MDMA-hyperthermia in emergency rooms. However, debate around its efficacy for this indication persists. OBJECTIVES: To investigate dantrolene as a treatment for illicit hyperthermia induced by psychomotor stimulant drugs, we examined how Ryanodex®, a concentrated formulation of dantrolene sodium produced by Eagle Pharmaceuticals, influences 3,4-methylenedioxymethamphetamine (MDMA)- and methamphetamine (METH)-induced hyperthermia in awake freely moving rats. We injected rats with moderate doses of MDMA (9 mg/kg) and METH (9 mg/kg) and administered Ryanodex® intravenously (6 mg/kg) after the development of robust hyperthermia (>2.5 °C) mimicking clinical acute intoxication. We conducted simultaneous temperature recordings in the brain, temporal muscle, and skin to determine the basic mechanisms underlying temperature responses. To assess the efficacy of dantrolene in attenuating severe hyperthermia, we administered MDMA to rats maintained in a warm ambient environment (29 °C), conditions which produce robust brain and body hyperthermia (>40 °C) and lethality. RESULTS: Dantrolene failed to attenuate MDMA- and METH-induced hyperthermia, though locomotor activity was significantly reduced. All animals maintained at warm ambient temperatures that received dantrolene during severe drug-induced hyperthermia died within or soon after the recording session. CONCLUSIONS: Our results suggest that dantrolene sodium formulations are not mechanistically suited to treat MDMA- and METH-induced hyperthermia.

Suppression of glutathione system and upregulation of caspase 3-dependent apoptosis mediate rohypnol-induced gastric injury.

Objectives: This study investigated the impact of rohypnol on gastric tissue integrity.Methods: Forty male Wistar rats were randomized into control, low dose rohypnol-treated, high dose rohypnol-treated, low dose rohypnol-treated recovery and high dose rohypnol-treated recovery groups.Results: Rohypnol caused significant rise in gastric malondialdehyde (MDA), oxidized glutathione (GSSG), nitric oxide (NO), tumour necrotic factor-α (TNF-α), and interleukin-6 (IL-6) levels. Also, rohypnol caused reductions in gastric reduced glutathione (GSH) (as well as GSH/GSSG), and activities of superoxide dismutase (SOD), catalase, glutathione-S-transferase (GST), glutathione peroxidase (GPx), cyclo-oxygenase (COX-2). Furthermore, rohypnol upregulated caspase 3 activity and induced gastric DNA damage, evident by a rise in 8-hydroxydeoxyguanosine (8-OHdG) and DNA fragmentation index (DFI) in gastric tissue. These alterations were coupled with reduced gastric weight and distorted gastric cytoarchitecture. Cessation of rohypnol caused a significant but not complete reversal of rohypnol-induced gastric damage.Conclusion: This study revealed that rohypnol induced gastric injury by suppressing glutathione content and COX-2 activity, and upregulating caspase 3-dependent apoptosis, which was partly reversed by rohypnol withdrawal.

Clinical Pharmacology of the Dietary Supplement Kratom (Mitragyna speciosa).

Kratom (Mitragyna speciosa) consists of over 40 alkaloids, with 2 of them, mitragynine and 7-OH-mitragynine (7-OH-MG) being the main psychoactive compounds. Mitragynine and 7-OH-mitragynine each target opioid receptors and have been referred to as atypical opioids. They exert their pharmacologic effects on the mu, delta, and kappa opioid receptors. In addition, they affect adrenergic, serotonergic, and dopaminergic pathways. Kratom has been touted as an inexpensive, legal alternative to standard opioid replacement therapy such as methadone and buprenorphine. Other uses for kratom include chronic pain, attaining a "legal high," and numerous central nervous system disorders, including anxiety, depression, and posttraumatic stress disorder. Kratom induces analgesia and mild euphoria, with a lower risk of respiratory depression or adverse central nervous system effects compared to traditional opioid medications. Nonetheless, kratom has been associated with both physical and psychological dependence, with some individuals experiencing classic opioid withdrawal symptoms upon abrupt cessation. Kratom use has been linked to serious adverse effects, including liver toxicity, seizures, and death. These risks are often compounded by polysubstance abuse. Further, kratom may potentiate the toxicity of coadministered medications through modulation of cytochrome P450, P-glycoprotein, and uridine diphosphate glucuronosyltransferase enzymes. In 2016, the US Drug Enforcement Administration took steps to classify kratom as a federal schedule 1 medication; however, due to public resistance, this plan was set aside. Until studies are conducted that define kratom's role in treating opioid withdrawal and/or other central nervous system conditions, kratom will likely remain available as a dietary supplement for the foreseeable future.

Metoprine, a histamine N-methyltransferase inhibitor, attenuates methamphetamine-induced hyperlocomotion via activation of histaminergic neurotransmission in mice.

Metoprine increases the content of histamine in brain by inhibiting histamine N-methyltransferase (HMT), a centrally acting histamine degrading enzyme. We present data demonstrating that pretreatment with metoprine attenuates the hyperlocomotive effects of METH in mice using a multi-configuration behavior apparatus designed to monitor four behavioral outcomes [horizontal locomotion, appetitive behavior (food access), and food and water intake]. Metoprine pretreatment itself induced hyperlocomotion in mice challenged with saline during the large part of light phase. The trend was also observed during the following dark phase. This is the first report that metoprine has a long-lasting locomotor stimulating property. Similarly, in a tail suspension test, a single injection of metoprine significantly reduced total time of immobility in mice, consistent with the idea that metoprine possesses motor stimulating properties. Metoprine pretreatment did not affect other aspects of behavior. Metoprine did not affect the appetitive and drinking behavior while exerted an effect on stereotypy. No stereotyped behavior was observed in mice pretreated with vehicle followed by METH, while stereotyped sniffing was observed in mice pretreated with metoprine followed by METH. The metoprine pretreatment attenuated METH-induced hyperlocomotion during the first 2 h of light phase, suggesting that metoprine-induced locomotor stimulating property might be different from that of METH. The hypothalamic content of histamine (but not its brain metabolite) was increased after metoprine or METH administration. Both METH and metoprine reduced dopamine and histamine turnover in the striatum and the nucleus accumbens and the hypothalamus, respectively, and there is a significant metoprine pretreatment x METH challenge interaction in the histamine turnover. It is likely that metoprine may attenuate METH-induced hyperlocomotion via activation of histaminergic neurotransmission. Metoprine also might induce a long-lasting locomotor stimulating effect via a putative mechanism different from that whereby METH induces the locomotor stimulating effect.

Maternal Oxycodone Treatment Results in Neurobehavioral Disruptions in Mice Offspring.

Opioid drugs are increasingly being prescribed to pregnant women. Such compounds can also bind and activate opioid receptors in the fetal brain, which could lead to long-term brain and behavioral disruptions. We hypothesized that maternal treatment with oxycodone (OXY), the primary opioid at the center of the current crisis, leads to later neurobehavioral disorders and gene expression changes in the hypothalamus and hippocampus of resulting offspring. Female mice were treated daily with 5 mg OXY/kg or saline solution (control; CTL) for two weeks before breeding and then throughout gestation. Male and female offspring from both groups were tested with a battery of behavioral and metabolic tests to measure cognition, exploratory-like, anxiety-like, voluntary physical activity, and socio-communication behaviors. qPCR analyses were performed for candidate gene expression patterns in the hypothalamus and hippocampus of OXY and CTL derived offspring. Developmental exposure to OXY caused socio-communication changes that persisted from weaning through adulthood. Such offspring also showed cognitive impairments, reduced voluntary physical activity, and weighed more than CTL counterparts. In the hippocampus, prenatal exposure to OXY caused sex-dependent differences in expression of genes encoding opioid receptors and those involved in serotonin signaling. OXY exposure induced changes in neuropeptide hormone expression and the epigenetic modulator, Dnmt3a, in the hypothalamus, which could result in epigenetic changes in this brain region. The findings suggest cause for concern that consumption of OXY by pregnant mothers may result in permanent neurobehavioral changes in their offspring. Further work is needed to determine the potential underpinning epigenetic mechanisms.

Study design criteria for regulatory-based drug control action: Drug discrimination.

This "methods paper" focusses on one specific and limited aspect of drug safety evaluations required for all new drug entities that affect the central nervous system - the drug discrimination (DD) assay. We focus on three critical factors involved in experimental design and protocol development for the conduct of DD studies for abuse liability risk assessment that comply with the Good Laboratory Practice Guidelines (GLPs). The selection of 1) the reference drug(s) choice, 2) training dose selection, and 3) the selected route-of-administration will determine the applicability of the data to meet the regulatory expectations of the 8-factors determinative of schedule control recommendations. The study conduct and resulting data submission to the FDA are intended for drug scheduling review by the Controlled Substances Staff in the Center for Drug Evaluation and Research (CDER) at the US Food & Drug Administration (FDA). These animal studies are required to meet the statutory requirements of the Controlled Substances Act of 1970. The abuse liability study is conducted during Phase II and III of human clinical trials. Procedural or method-based errors this late in drug development can result in a significant economic and business threat to the program.

Nutritional parameters and lifestyle practices of people who use drugs undergoing treatment for recovery in Lebanon: a descriptive study.

Drug use disorder is a major public health problem. Once people who use drugs (PWUD) are referred to treatment, addressing their lifestyle practices and improving their quality of life improves treatment outcomes. The present study assessed the nutritional status and lifestyle practices among PWUD undergoing treatment for recovery in Lebanon. Furthermore, it explored significant differences in these parameters depending on the offered treatment modality, namely opioid substitution treatment (OST) and rehabilitation. In total, 187 PWUD undergoing treatment for recovery participated in this cross-sectional study. Nutritional status and anthropometrics, dietary intake, nutrition knowledge, food addiction, biochemical parameters, sleep and physical activity were measured using validated tools. Of the participants, 88⋅8 % were well nourished based on the Subjective Global Assessment. In total, 67 % gained weight during treatment placing them in the overweight category. This increase in weight was significantly higher in the rehabilitation group. It came in parallel with higher protein and energy intakes, higher rate of food addiction, and poor nutrition knowledge. Biochemical parameters, including fasting blood sugar, total protein, lipid profile and white blood cell count, were in the normal ranges. Moreover, the majority of participants exhibited poor quality sleep that was accentuated among the participants undergoing rehabilitation, in addition to activity levels that were mainly low in the OST group. PWUD undergoing treatment for recovery in Lebanon are subject to various vulnerability factors creating challenges to treatment. Longitudinal assessments to better understand health problems arising during treatment and to identify the components of a comprehensive health promotion intervention during treatment for recovery are needed.

Cannabinoid Hyperemesis Syndrome: A Review of the Presentation and Treatment.

After the increasing legalization of cannabis, there has been a rising trend in cannabis consumption, especially among heavy users. Cannabinoid hyperemesis syndrome is a syndrome of cyclic vomiting related to chronic cannabis use. The difficulty of diagnosis and treatment of this syndrome has led to a disproportionately high use of health care resources. Although the exact mechanism of cannabinoid hyperemesis syndrome is still unknown, patients typically progress through prodromal, hyperemetic, and recovery phases. Persistent vomiting in a patient who reports relief with hot showers should trigger the consideration of cannabinoid hyperemesis syndrome as a possible diagnosis. For treatment, antipsychotics such as haloperidol or droperidol have been shown to be more effective than conventional antiemetics for symptom control. Capsaicin should also be considered, given its positive efficacy and low adverse-effect profile. Providers must be aware of cannabinoid hyperemesis syndrome, its diagnosis, and treatment, given the increasing prevalence. Further research is required to elicit the exact mechanism and additional therapies for this syndrome.

Choosing Between a Rock and the Pot Place.

In the evolving field of medicinal cannabis, there are many questions and concerns broached by patients to which health care providers cannot respond with anything other than anecdotal evidence. Many simple knowledge gaps persist due to barriers to high-quality research at the institutional and state levels: barriers that, in turn, stem from the federal designation of cannabis as an illegal substance. These perspectives of a California-based pain physician on the approach to the cannabis-curious pain patient highlight the necessity of a change in the classification of cannabis to streamline research as to the benefits and risks of this now ubiquitous substance.

Prevalence and description of kratom (Mitragyna speciosa) use in the United States: a cross-sectional study.

BACKGROUND AND AIMS: Mitragyna speciosa ('kratom') contains mu opioid partial agonists. It is widely available, and occasionally used as a home remedy for opioid use disorder. The Drug Enforcement Agency considers kratom a drug of concern; however, prevalence of use and role in drug misuse are unknown. This study aimed to characterize kratom use in the United States. DESIGN: Cross-sectional Survey of Non-Medical Use of Prescription Drugs (NMURx) Program, 2018 third quarter and 2019 first quarter. SETTING: A validated non-probability online survey in the United States. PARTICIPANTS: A total of 59 714 respondents aged 18 years or older, weighted to represent the adult US population (n = 252 063 800). MEASUREMENTS: In addition to prevalence of past-year kratom and other drug use, behavior proportions were estimated. The Drug Abuse Screening Test (DAST-10) estimated consequences of drug abuse. FINDINGS: The estimated prevalence of past-year kratom use in the adult US population was 0.8% [95% confidence interval (CI) = 0.7-0.9], representing 2 031 803 adults. Life-time prevalence was 1.3% (95% CI = 1.2-1.4), representing 3 353 624 adults. Kratom users were younger (mean 35 years, P < 0.001), with higher proportions of males (61.0 versus 48.6%, P < 0.001), students (14.1 versus 7.5%, P < 0.001) and health-care professionals (9.7 versus 4.5%, P < 0.001) and fewer bachelor's/advanced degree graduates (33.4 versus 42.6%, P < 0.001) compared with non-users. Results were inconclusive on whether there was a difference in kratom use by race, household income or employment status. Among those with past-year kratom use, 36.7% (95% CI = 32.1-41.3) non-medically used prescription opioids, 21.7% (95% CI = 18.0-25.5) used illicit opioids, 54.4% (95% CI = 49.5-59.3) used another illicit drug and 67.1% (95% CI = 62.5-71.8) used cannabis. The DAST-10 profile was more often substantial/severe in kratom users (21 versus 1%, P < 0.001) compared with non-users. CONCLUSIONS: Estimated United States past-year prevalence of kratom use is 0.8%, and kratom users tend to have more serious substance abuse profiles than non-users or users of cannabis, alcohol or cigarettes. To our knowledge, this is the first description of kratom use at the national level.

The development of a nomogram to determine the frequency of elevated risk for non-medical opioid use in cancer patients.

OBJECTIVE: Non-medical opioid use (NMOU) is a growing crisis. Cancer patients at elevated risk of NMOU (+risk) are frequently underdiagnosed. The aim of this paper was to develop a nomogram to predict the probability of +risk among cancer patients receiving outpatient supportive care consultation at a comprehensive cancer center. METHOD: 3,588 consecutive patients referred to a supportive care clinic were reviewed. All patients had a diagnosis of cancer and were on opioids for pain. All patients were assessed using the Edmonton Symptom Assessment Scale (ESAS), Screener and Opioid Assessment for Patients with Pain (SOAPP-14), and CAGE-AID (Cut Down-Annoyed-Guilty-Eye Opener) questionnaires. "+risk" was defined as an SOAPP-14 score of ≥7. A nomogram was devised based on the risk factors determined by the multivariate logistic regression model to estimate the probability of +risk. RESULTS: 731/3,588 consults were +risk. +risk was significantly associated with gender, race, marital status, smoking status, depression, anxiety, financial distress, MEDD (morphine equivalent daily dose), and CAGE-AID score. The C-index was 0.8. A nomogram was developed and can be accessed at https://is.gd/soappnomogram. For example, for a male Hispanic patient, married, never smoked, with ESAS scores for depression = 3, anxiety = 3, financial distress = 7, a CAGE score of 0, and an MEDD score of 20, the total score is 9 + 9+0 + 0+6 + 10 + 23 + 0+1 = 58. A nomogram score of 58 indicates the probability of +risk of 0.1. SIGNIFICANCE OF RESULTS: We established a practical nomogram to assess the +risk. The application of a nomogram based on routinely collected clinical data can help clinicians establish patients with +risk and positively impact care planning.

Rohypnol-induced sexual dysfunction is via suppression of hypothalamic-pituitary-testicular axis: An experimental study in rats.

Sexual activity is an essential part of reproductive functions and needed for the maintenance of fertility. Drugs, particularly substances of abuse, impair male reproductive function either by interrupting hormonal functions or through the nonhormonal pathways. This study evaluated the impact of Rohypnol use in sexual behaviour. Materials and methods: Thirty adult male Wistar rats of comparable weights (180-200 g) were randomly allocated into three groups, the control and low-dose and high-dose Rohypnol-treated groups. The control group received 0.5 ml of distilled water, while the low- and high-dose Rohypnol-treated groups received 2 mg/kg b.w and 4 mg/kg b.w of Rohypnol via oral lavage once daily for 28 days. Rohypnol significantly increased mount latency, intromission latency, ejaculation latency and post-ejaculatory interval, as well as lowered mount frequency, intromission frequency and ejaculation frequency. Rohypnol-induced sexual dysfunction was found to be associated with significant suppression of circulatory follicle-stimulating hormone, luteinising hormone, testosterone and oestrogen. The present study reveals that Rohypnol induces sexual dysfunction through suppression of hypothalamic-pituitary-testicular axis. It also implicates Rohypnol as a potential candidate for drug-induced infertility.

Analgesic opioid use disorders in patients with chronic non-cancer pain: A holistic approach for tailored management.

Chronic pain is a major public health issue that frequently leads to analgesic opioid prescriptions. These prescriptions could cause addiction issues in high-risk patients with associated comorbidities, especially those of a psychiatric, addictive, and social nature. Pain management in dependent patients is complex and is yet to be established. By combining the views of professionals from various specialties, we conducted an integrative review on this scope. This methodology synthesizes knowledge and results of significant practical studies to provide a narrative overview of the literature. The main results consisted in first proposing definitions that could allow shared vocabulary among health professionals regardless of their specialties. Next, a discussion was conducted around the main strategies for managing prescription opioid dependence, as well as pain in the context of opioid dependence and associated comorbidities. As a conclusion, we proposed to define the contours of holistic management by outlining the main guidelines for creating a multidisciplinary care framework for multi-comorbid patients with chronic pathologies.

Morphine-mediated release of miR-138 in astrocyte-derived extracellular vesicles promotes microglial activation.

Opioids, such as morphine, are the mainstay for the management of postsurgical pain. Over the last decade there has been a dramatic increase in deaths related to opioid overdose. While opioid abuse has been shown to result in increased neuroinflammation, mechanism(s) underlying this process, remain less understood. In recent years, microRNAs have emerged as key mediators of gene expression regulating both paracrine signaling and cellular crosstalk. MiRNAs constitute the extracellular vesicle (EV) cargo and can shuttle from the donor to the recipient cells. Exposure of human primary astrocytes to morphine resulted in induction and release of miR-138 in the EVs isolated from conditioned media of cultured astrocytes. Released EVs were, in turn, taken up by the microglia, leading to activation of these latter cells. Interestingly, activation of microglia involved binding of the GUUGUGU motif of miR138 to the endosomal toll like receptor (TLR)7, leading, in turn, to cellular activation. These findings were further corroborated in vivo in wildtype mice wherein morphine administration resulted in increased microglial activation in the thalamus. In TLR7-/- mice on the other hand, morphine failed to induce microglial activation. These findings have ramifications for the development of EV-loaded anti-miRNAs as therapeutics for alleviating neuroinflammation in opioids abusers.

Pregabalin induced reproductive toxicity and body weight changes by affecting caspase3 and leptin expression: Protective role of wheat germ oil.

Pregabalin (PGB) drug abuse is common among the youth. It substituted tramadol before its recent schedule as a controlled drug since April 2019. PGB is an antiepileptic drug acting on the central nervous system. It blocks calcium channels regulating the action of neurotransmitters and causing prolonged depolarization. The present study aimed to investigate the toxic effect of long term pregabalin abuse on the reproductive function and body weight in both male and female albino rats and to evaluate the ameliorative effect of wheat germ oil (WGO). Forty-eight rats were randomly divided into eight groups. The first four groups were males and they were treated as follows: control group (1.5 mL saline), WGO group (1.5 mL L/kg), PGB group (300 mg/kg), and protective group (PGB + WGO). All doses were administrated once per day for 60 days by gastric gavage. The second four groups were females. They were divided and treated the same as the male groups. Pregabalin caused significant weight loss, decreased serum triglyceride level, and increased leptin gene expression in all rats. PGB affected male rats reproduction by decreasing total testosterone serum level and inhibiting spermatogenesis. Reproductive toxicity in females was caused by decreasing pituitary steroids, increasing gonadal hormones, and increasing the number of atretic ovarian follicles. Mechanism of toxicity may be attributed to the PGB oxidative stress effect that induced apoptosis and caused diffuse gonadal atrophy. WGO showed a protective effect on PGB induced toxicity as all measured parameters were relatively improved.